Non-irritating testosterone emulsions

ABSTRACT

Disclosed herein are emulsions comprising testosterone or related androgens, castor oil, cyclodextrin, Pemulen TR-2, Polyoxyl 40, and other ingredients. The compositions are useful for treating keratoconjunctivitis sicca and meibomian gland disease.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No. 17/004,218, filed Aug. 27, 2020, which is a continuation of U.S. patent application Ser. No. 15/948,771, filed Apr. 9, 2018, now U.S. Pat. No. 10,780,098, issued Sep. 22, 2020, which is a continuation of U.S. patent application Ser. No. 14/216,464, filed Mar. 17, 2014, now U.S. Pat. No. 9,937,188, issued Apr. 10, 2018, which is a continuation-in-part of U.S. patent application Ser. No. 13/357,779, filed Jan. 25, 2012, now U.S. Pat. No. 9,119,772, issued Sep. 1, 2015, which claims priority to U.S. Provisional Patent Application No. 61/436,274 filed Jan. 26, 2011, the entirety of both applications are incorporated herein by reference.

U.S. patent application Ser. No. 14/216,464, filed Mar. 17, 2014, now U.S. Pat. No. 9,937,188, issued Apr. 10, 2018, also claims the benefit of priority of U.S. Provisional Patent Application No. 61/800,621, filed Mar. 15, 2013, the entirety of which is hereby incorporated by reference.

BACKGROUND Field

Disclosed herein are emulsions comprising testosterone or related androgens, castor oil, cyclodextrin, Pemulen TR-2, Polyoxyl 40, and other ingredients. The compositions are useful for treating keratoconjunctivitis sicca and meibomian gland disease.

Description of the Related Art

Blepharitis is a disorder of the meibomian glands, which produce the lipid component of tear film. Both the upper and lower eye lids contain 30-40 glands, located beneath the skin. The glandular pores open just behind the base of the eye lashes on the eye lid margin. With blepharitis, the glands become inflamed and the pores become blocked. Symptoms of blepharitis include eye irritation, soreness, redness and an accumulation of matter on the eyelids. Patients may also experience dry eye as well. As a result of these symptoms, blepharitis is commonly misdiagnosed as conjunctivitis or dry eye.

In certain cases, a local androgen deficiency can cause blepharitis. Topical compositions containing an androgen would be desirable for the treatment of blepharitis.

SUMMARY

The disclosure provides compositions and methods for treating one or more ocular conditions.

In one embodiment, a composition is provided comprising a physiologically effective amount of an androgen, wherein said composition is suitable for topical administration to an eye.

In another embodiment, a method for treating an ocular condition resulting from an androgen deficiency is disclosed. The method comprises administering an effective amount of an ophthalmic composition comprising a physiologically effective amount of an androgen, wherein said composition is suitable for topical administration to an eye, and wherein at least one symptom of the ocular condition is alleviated.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows ocular discomfort in 3 groups of female rabbits treated in the left eye with a topical ocular drop (˜30 μL) of testosterone formulations at a concentration of 0.03%, 0.1%, or 0.3%, 3 times daily (at 3-hour intervals) for 7 consecutive days.

DETAILED DESCRIPTION

The disclosure provides an ophthalmic composition comprising a physiologically effective amount of an androgen, wherein said composition is suitable for topical administration to an eye.

Disclosed herein are emulsions comprising testosterone or related androgens at a concentration between about 0.01% (w/w) and about 5.0% (w/w), castor oil at a concentration between about 0.10% (w/w) and about 5% (w/w), sulfobutyl ether-β-cyclodextrin at a concentration between about 0.25% (w/w) and about 10% (w/w), Pemulen® TR-2 at a concentration between about 0.01% (w/w) and about 5% (w/w), and polyoxyl 40 stereate at a concentration between about 0.01% (w/w) and about 5% (w/w).

A method for treating an ocular condition associated with an androgen deficiency is also disclosed herein. The method comprises administering an effective amount of an ophthalmic composition comprising a physiologically effective amount of an androgen, wherein said composition is suitable for topical administration to an eye, and wherein at least one symptom of the ocular condition is alleviated.

The compositions disclosed herein comprise an androgen. As used herein, unless otherwise specified, the term “androgen” includes all testosterone and testosterone containing moieties, endogenous and synthetic, as well as isomers, analogues, esters, and combinations thereof. The androgen can be an endogenously produced steroidal androgen, which includes, but is not limited to, testosterone (i.e., (17β)-17-hydroxyandrost-4-ene-3-one), dihydrotestosterone (DHT), dehydroepiandrosterone, androstenedione, androstenediol, and androsterone. Further included are testosterone-containing moieties, for example, esters of testosterone, such as the cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocarporate, enanthate, phenylactate, acetate, buciclate, heptanoate, caprate, isocaprate, and decanoate esters, and other synthetic androgens such as oxymetholone, 17α-methylnortestosterone, and 7-methylnortestosterone and its acetate ester.

The ocular condition can be any condition of an eye, eye lid, gland, or skin surrounding the eye resulting from a local or systemic androgen deficiency. In certain embodiments, the ocular condition is blepharitis. Androgen deficiency can occur for a variety of reasons, for instance, during menopause or as a result of the natural aging process. Androgen deficiency can be due to a disease or condition, such as Sjögren's syndrome.

The patient to be treated can be any mammal of any age, or gender. The mammal can be a human, dog, cat, sheep, cow, etc. in need of treatment. In certain embodiments, the patient to be treated is a human, male or female.

A physiologically effective amount refers to an amount of a substance that is sufficient to achieve the intended purpose or effect. Various biological factors can influence the amount required to be effective, for instance, age, gender, severity of the underlying condition, and overall health of the patient. As used herein, a dosage is considered effective if it prevents, reduces, or eliminates the symptoms associated with the ocular condition to be treated.

The androgen can be present in the ophthalmic compositions described herein in an amount of about 0.001% to about 5% by weight (w/w), or from about 0.09% to about 2% by weight, or from about 0.01% to about 1.0% (w/w).

In some embodiments, compositions of the invention comprise from about 0.01% (w/w) to about 5.0% (w/w) testosterone or testosterone-containing moiety. In one embodiment, the composition comprises from about 0.01% (w/w) to about 5.0% (w/w) testosterone. In another embodiment, the composition comprises from about 0.01% (w/w) to about 1.0% (w/w) testosterone. In another embodiment, the composition comprises from about 0.01% (w/w) to about 0.5% (w/w) testosterone.

In other embodiments, the compositions comprise about 0.01% (w/w), about 0.015% (w/w), about 0.02% (w/w), about 0.025% (w/w), about 0.03% (w/w), about 0.035% (w/w), about 0.04% (w/w), about 0.045% (w/w), about 0.05% (w/w), about 0.055% (w/w), about 0.06% (w/w), about 0.065% (w/w), about 0.07% (w/w), about 0.075% (w/w), about 0.08% (w/w), about 0.085% (w/w), about 0.09% (w/w), about 0.095% (w/w), about 0.1% (w/w), about 0.15% (w/w), about 0.2% (w/w), about 0.25% (w/w), about 0.3% (w/w), about 0.35% (w/w), about 0.4% (w/w), about 0.45% (w/w), about 0.5% (w/w), about 0.55% (w/w), about 0.6% (w/w), about 0.65% (w/w), about 0.7% (w/w), about 0.75% (w/w), about 0.8% (w/w), about 0.85% (w/w), about 0.9% (w/w), about 0.95% (w/w), or about 1.0% (w/w) testosterone.

The disclosed compositions can be emulsions, solutions, suspensions, gels, ointments, occlusive films, or a sustained release films and they can be preserved or non-preserved formulations. The compositions can be formulated as eye drops, creams, ointments, and films that can be applied to an eye. The formulations can be administered to the eye, the upper eye lid, the lower eye lid, or a combination thereof. Topical administration of the compositions provides treatment at the site of the condition with minimal systemic levels of the medicament.

Listed in Table 1 are examples of formulation ingredients and exemplary concentrations.

TABLE 1 Composition Function Ingredient (% w/w) Active testosterone 0.01-1.0  Thickener carbomer, sodium  0-3.0 carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, zanthan gum Neutralizing sodium hydroxide, organic bases  0-2.0 Agent Emulsifier polysorbate 20, polysorbate 40,  0-2.0 polysorbate 60, polysorbate 80, POE-40-stearate, Pemulen ® and other polymeric emulsifiers. Lipophilic castor oil, squalane, isostearyl 0-80 Vehicle isostearate, isopropyl myristate,, mineral oil, silicone oil, caprylic/capric triglycerides, cetyl alcohols, stearyl alcohols Co-solvents diethylene glycol monoethyl ether, 0-80 propylene glycol, dipropylene glycol dimethyl ether, diethylene glycol, dipropylene glycol Buffering Agent sodium citrate dihydrate, boric acid, 0-2  monosodium phosphate, monohydrate, sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate Tonicity Agent Glycerin, erythritol, mannitol, 0-3  potassium chloride, sodium chloride, Solubilizer Cyclodextin, alpha-cyclodextrin, 0-10 beta-cyclodextrin, gamma- cyclodextrin, hydroxypropyl-beta- cyclodextrin, Sulfobutyl ether-β- cyclodextrin (Captisol ®) Demulcent carboxymethylcellulose sodium, 0-10 hydroxypropyl methylcellulose hydroxyethyl cellulose, methylcellulose, polyvinyl alcohol, povidone, glycerin, propylene glycol, PEG 300, PEG 400 Preservative benzalkonium chloride, PURITE ®,  0-2.0 and other ophthalmic preservatives Plasticizer Silicone oils, isostearyl alcohol, cetyl  0-5.0 alcohol, glycerin Occlusive Agent silicone oils, petrolatum, waxes 0-80 Film Former acrylate/octylacrylamide copolymer, 0-10 poly(ethyl acrylate, methyl methacrylate), chitosan, polyvinyl alcohol, polyisobutylene, polyvinylpyrrolidone-vinyl acetate copolymer, silicon gum, polyvinylpyrrolidone, other sustained release polymeric films Vehicle water, saline 0-99

The emulsions of the disclosed compositions can be stabilized using one or more polyelectrolytes from the family of cross-linked polyacrylates, such as carbomers and PEMULEN® (Lubrizol). Pemulens are high molecular weight co-polymers of acrylic acid and a long chain alkyl methacrylate cross-linked with allyl ethers of pentaerythritol. Pemulen® TR-2 is a C10-30 alkyl acrylate crosspolymer containing a higher level of hydrophobic groups than other Pemulen® polymers. They contain not less than about 52% and not more than about 62% of carboxylic acid groups. The viscosity of a neutralized 1.0% aqueous dispersion is between about 9,500 and about 26,500 centipoise. Additional emulsifiers include, but are not limited to, polysorbate-80, POE-40-Stearate, polysorbate-20, polysorbate 40, polysorbate-60, and a combination thereof in an amount of about 0% to about 4% or about 0.01 to about 2.0% by weight of the composition.

In one embodiment, the composition of the invention comprises between about 0.1% (w/w) and about 5% (w/w) of Pemulen or Pemulen TR-2. In another embodiment, the composition of the invention comprises between about 0.1% (w/w) and about 1% (w/w) of Pemulen or Pemulen TR-2. In another embodiment, the composition of the invention comprises between about 0.1% (w/w) and about 0.5% (w/w) of Pemulen or Pemulen TR-2. In another embodiment, the composition comprises about 0.1% (w/w), about 0.15% (w/w), about 0.2% (w/w), about 0.25% (w/w), about 0.3% (w/w), about 0.35% (w/w), about 0.4% (w/w), about 0.45% (w/w), about 0.5% (w/w), about 0.55% (w/w), about 0.6% (w/w), about 0.65% (w/w), about 0.7% (w/w), about 0.75% (w/w), about 0.8% (w/w), about 0.85% (w/w), about 0.9% (w/w), about 0.95% (w/w), about 1% (w/w), about 1.5% (w/w), about 2% (w/w), about 2.5% (w/w), about 3% (w/w), about 3.5% (w/w), about 4% (w/w), about 4.5% (w/w), or about 5% (w/w) of Pemulen or Pemulen TR-2.

In one embodiment, the composition of the invention comprises between about 0.1% (w/w) and about 5% (w/w) of Polyoxyl 40 stearate. In another embodiment, the composition of the invention comprises between about 0.1% (w/w) and about 1% (w/w) of Polyoxyl 40 stearate. In another embodiment, the composition of the invention comprises between about 0.1% (w/w) and about 0.5% (w/w) of Polyoxyl 40 stearate. In another embodiment, the composition comprises about 0.1% (w/w), about 0.15% (w/w), about 0.2% (w/w), about 0.25% (w/w), about 0.3% (w/w), about 0.35% (w/w), about 0.4% (w/w), about 0.45% (w/w), about 0.5% (w/w), about 0.55% (w/w), about 0.6% (w/w), about 0.65% (w/w), about 0.7% (w/w), about 0.75% (w/w), about 0.8% (w/w), about 0.85% (w/w), about 0.9% (w/w), about 0.95% (w/w), about 1% (w/w), about 1.5% (w/w), about 2% (w/w), about 2.5% (w/w), about 3% (w/w), about 3.5% (w/w), about 4% (w/w), about 4.5% (w/w), or about 5% (w/w) of Polyoxyl 40 stearate.

In one embodiment, the composition of the invention comprises between about 0.1% (w/w) and about 5% (w/w) of Polysorbate 80. In another embodiment, the composition of the invention comprises between about 0.1% (w/w) and about 1% (w/w) of Polysorbate 80. In another embodiment, the composition of the invention comprises between about 0.1% (w/w) and about 0.5% (w/w) of Polysorbate 80. In another embodiment, the composition comprises about 0.1% (w/w), about 0.15% (w/w), about 0.2% (w/w), about 0.25% (w/w), about 0.3% (w/w), about 0.35% (w/w), about 0.4% (w/w), about 0.45% (w/w), about 0.5% (w/w), about 0.55% (w/w), about 0.6% (w/w), about 0.65% (w/w), about 0.7% (w/w), about 0.75% (w/w), about 0.8% (w/w), about 0.85% (w/w), about 0.9% (w/w), about 0.95% (w/w), about 1% (w/w), about 1.5% (w/w), about 2% (w/w), about 2.5% (w/w), about 3% (w/w), about 3.5% (w/w), about 4% (w/w), about 4.5% (w/w), or about 5% (w/w) of Polysorbate 80.

In some embodiments, the composition comprises a lipophilic vehicle such as, for example, castor oil, squalane, diethylene glycol monoethyl ether, propylene glycol, isostearyl isostearate, isopropyl myristate, dipropylene glycol dimethyl ether, diethylene glycol, dipropylene glycol, mineral oil, silicone oil, caprylic/capric triglycerides, cetyl alcohols, stearyl alcohols, and a combination thereof. The lipophilic vehicle can be present in an amount of about 0% to about 85%, or about 1% to about 50%, or about 2% to about 15% of the composition by weight.

The compositions of the invention may further comprise, as a lipophilic vehicle, a plant oil. The plant oil can provide the oil phase of the emulsion. Suitable plant oils include, for example, anise oil, castor oil, clove oil, cassia oil, cinnamon oil; almond oil, corn oil, arachis oil, cottonseed oil, safflower oil, maize oil, linseed oil, rapeseed oil, soybean oil, olive oil, caraway oil, rosemary oil, peanut oil, peppermint oil, sunflower oil, eucalyptus oil, sesame oil, coriander oil, lavender oil, citronella oil, juniper oil, lemon oil, orange oil, clary sage oil, nutmeg oil, tea tree oil, coconut oil, tallow oil, and lard.

In one embodiment, the composition comprises between about 0.1% (w/w) and about 5% (w/w) of a plant oil. In another embodiment, the composition comprises between about 0.1% (w/w) and about 1% (w/w) of a plant oil. In another embodiment, the composition of the invention comprises between about 0.1% (w/w) and about 0.5% (w/w) of a plant oil. In another embodiment, the composition comprises about 0.1% (w/w), about 0.15% (w/w), about 0.2% (w/w), about 0.25% (w/w), about 0.3% (w/w), about 0.35% (w/w), about 0.4% (w/w), about 0.45% (w/w), about 0.5% (w/w), about 0.55% (w/w), about 0.6% (w/w), about 0.65% (w/w), about 0.7% (w/w), about 0.75% (w/w), about 0.8% (w/w), about 0.85% (w/w), about 0.9% (w/w), about 0.95% (w/w), about 1% (w/w), about 1.5% (w/w), about 2% (w/w), about 2.5% (w/w), about 3% (w/w), about 3.5% (w/w), about 4% (w/w), about 4.5% (w/w), or about 5% (w/w) of a plant oil.

The disclosed compositions can comprise a neutralizing agent such as sodium hydroxide and organic bases in an amount of about 0 to about 2.5% by weight of the composition.

In certain embodiments, the composition may include a demulcent such as carboxymethylcellulose sodium, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose, polyvinyl alcohol, povidone, glycerin, propylene glycol, PEG 300, PEG 400, and a combination thereof. The demulcent can be present in an amount of about 0 to about 10%, or about 2%, 5%, 7%, or 9%, by weight of the composition.

In some embodiments, the composition comprises a tonicity agent such as sodium chloride, glycerin, mannitol, potassium chloride, erythritol, and a combination thereof, in an amount of about 0 to about 4% or about 0.01% to about 3% by weight of the composition.

In some embodiments, the composition may include one or more buffering agents. Suitable buffering agents include, but are not limited to, phosphates, citrates, acetates, borates, and combinations thereof. The amount of buffer component employed is sufficient to maintain the pH of the composition in a range of about 6 to about 8, or from about 6.5 to about 7.5. In certain embodiments, the buffer is present in an amount of about 0 to about 2.0% by weight of the composition.

In certain embodiments, the composition includes a thickener or viscosity agent. The viscosity agent can be selected from the group consisting of carbomer, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, zanthan gum, and a combination thereof. The viscosity agent can be present in an amount of about 0% to about 4% or about 0.01% to about 3.0% by weight of the composition.

In certain embodiments, the composition includes a solubilizer or solubility enhancing agent. The solubilizer or solubility enhancing agent can be selected from the group consisting of Cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, Sulfobutyl ether-β-cyclodextrin (Captisol®) and a combination thereof. The solubilizer or solubility enhancing agent can be present in an amount of about 0% to about 10%. In some embodiments, the solubilizer or solubility enhancing agent can be present in an amount of about 0.01% to about 7.0%. In some embodiments, the solubilizer or solubility enhancing agent can be present in an amount of about 0.1 to about 4% by weight of the composition.

As mentioned above, in some embodiments, the composition can comprise a cyclodextrin. Examples of cyclodextrins and are disclosed in U.S. Pat. Nos. 5,376,645, 5,134,127, 7,635,773, 7,629,331, and 8,049,003, the entire disclosures of all of which are incorporated herein by reference.

In one embodiment, the composition comprises between about 0.1% (w/w) and about 10% (w/w) of a cyclodextrin. In another embodiment, the composition comprises between about 0.1% (w/w) and about 5% (w/w) of a cyclodextrin. In another embodiment, the composition comprises between about 0.1% (w/w) and about 1% (w/w) of a cyclodextrin. In another embodiment, the composition comprises about 0.1% (w/w), about 0.15% (w/w), about 0.2% (w/w), about 0.25% (w/w), about 0.3% (w/w), about 0.35% (w/w), about 0.4% (w/w), about 0.45% (w/w), about 0.5% (w/w), about 0.55% (w/w), about 0.6% (w/w), about 0.65% (w/w), about 0.7% (w/w), about 0.75% (w/w), about 0.8% (w/w), about 0.85% (w/w), about 0.9% (w/w), about 0.95% (w/w), about 1% (w/w), about 1.25% (w/w), about 1.5% (w/w), about 2% (w/w), about 2.25% (w/w), about 2.5% (w/w), about 2.75% (w/w), about 3% (w/w), about 3.25% (w/w), about 3.5% (w/w), about 3.75% (w/w), about 4.0% (w/w), about 4.25% (w/w), about 4.5% (w/w), about 4.75% (w/w), about 5.0% (w/w), about 5.25% (w/w), about 5.5% (w/w), about 5.75% (w/w), about 6.0% (w/w), about 6.25% (w/w), about 6.5% (w/w), about 6.75% (w/w), about 7.0% (w/w), about 7.25% (w/w), about 7.5% (w/w), about 7.75% (w/w), about 8.0% (w/w), about 8.25% (w/w), about 8.5% (w/w), about 8.75% (w/w), 9.0% (w/w), about 9.25% (w/w), about 9.5% (w/w), about 9.75% (w/w), or about 10.0% (w/w) of a cyclodextrin. In one embodiment the cyclodextrin is sulfobutyl ether-β-cyclodextrin, at any of the foregoing concentrations.

The composition can be administered topically in the form of a solution (i.e., drops), cream, ointment, film, or the like. The composition can be administered to a left eye, a right eye, or both eyes. When the composition is administered as a solution, a drop of solution should disperse readily upon contact with a tear solution.

The compositions of, or used in, the present disclosure may include one or more other components in amounts effective to provide one or more useful properties and/or benefits. For example, although the present compositions may be substantially free of added preservative components, in other embodiments, the present compositions include effective amounts of preservative components. Examples of such preservative components include, without limitation, PURITE® (Allergan, Irvine, Calif.), quaternary ammonium preservatives such as benzalkonium chloride (“BAC” or “BAK”) and polyoxamer; biguanidebigunanide preservatives such as polyhexamethylene biguanidebiguandide (PHMB); methyl and ethyl parabens; hexetidine; chlorite components, such as stabilized chlorine dioxide, metal chlorites and the like; other ophthalmically acceptable preservatives and mixtures thereof. The concentration of the preservative component, if any, in the present compositions is a concentration effective to preserve the composition, and (depending on the nature of the particular preservative used) is often and generally used in a range of about 0% to about 4.0% by weight or about 0.1% to about 2.0% by weight of the composition.

In certain embodiments, the composition can be in the form of a film, such as an occlusive film or a sustained release film. Also contemplate dare liquids that dry to form films. Where films are employed, the films will be in the range of at least about 0.5 mm×0.5 mm, usually about 3-10 mm×5-10 mm with a thickness of about 0.1-1.0 mm for ease of handling. The size and form of the film can be used to control the rate of release. Such compositions can comprise one or more film forming agents such as acrylate/octylacrylamide copolymer, poly(ethyl acrylate, methyl methacrylate), chitosan, polyvinyl alcohol, polyisobutylene, polyvinylpyrrolidone-vinyl acetate copolymer, silicon gum, polyvinylpyrrolidone, other sustained release polymeric films, and a combination thereof. The film forming agent can be present in an amount of about 0% to about 10% by weight of the composition.

The frequency, duration, and dosage of the administration are determined by the prescribing physician. The dosage can vary depending on the dosage form. When the composition is a solution, for example, 1, 2, 3, or more drops can be administered per eye per administration. Frequency of administration can be one or more times daily (such as once, twice, three, or four or more times daily), bi-weekly, and/or monthly. Duration of administration can continue until the condition to be treated is resolved, that is, until one or more symptoms of the ocular condition are reduced or eliminated. Accordingly, the composition can be administered for hours, days, weeks, months, and years.

A symptom is considered to be alleviated if it is prevented, reduced or eliminated. A symptom is prevented in a patient that typically experiences a particular symptom with the ocular condition (or if patients similarly situated typically experience a particular symptom) and the patient does not experience the onset of the symptom following administration of the disclosed composition. A reduction of a symptom is considered achieved if there is a 5%, 10%, 20%, 50%, 75%, 90% or more reduction in the severity or duration of one or more symptom associated with the ocular condition, in a patient. An elimination of one or more symptoms associated with the ocular condition is achieved when it ceases to be present or substantially present in a patient.

Certain embodiments of the disclosed compositions incorporate a local anesthetic, which can be selected from the group of ambucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethysoquin, dimethocaine, diperodon, dycyclonine, ecgonidine, ecgonine, ethyl chloride, etidocaine, beta-eucaine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, naepaine, octacaine, orthocaine, oxethazaine, parethoxycaine, phenacaine, phenol, piperocaine, piridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, psuedococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine, zolamine, and salts thereof. The concentration of the local anesthetic in the compositions described herein can be therapeutically effective, meaning the concentration is adequate to provide a therapeutic benefit without inflicting harm to the patient.

The compositions can further comprise an opthalmologically acceptable anti-inflammatory agent, such as any non-steroidal anti-inflammatory drug (NSAID) in an amount effective to reduce inflammation in an eye. Non-limiting examples include agents that inhibit the cycloxygenase (COX)-1 and/or -2 enzyme, including but not limited to propionic acids such as naproxen, flurbiprofen, oxaprozin, ibuprofen, ketoprofen, fenoprofen; ketorolac tromethamine; acetic acid derivatives such as sulindac, indomethacin, and etodolac; phenylacetic acids such as diclofenac, bromfenac, and suprofen; arylacetic prodrugs such as nepafenac, and amfenac; salicyclic acids, such as aspirin, salsalate, diflunisal, choline magnesium trisalicylate (CMT); para-aminophenol derivatives such as acetaminophen; naphthylalkanones such as nabumetone; enolic acid derivatives such as piroxicam and meloxicam; femanates such as mefenamic acid, meclofenamate and flufenamic acid; pyrroleacetic acids such as tolmetin; and pyrazolones such as phenylbutazone; COX-2 selective inhibitors such as celecoxib, valdecoxib, parecoxib, etoricoxib, and luaricoxib; including all esters and pharmaceutically acceptable salts thereof. A steroidal anti-inflammatory agent can also be incorporated, in certain embodiments, and can include, without limitation, hydrocortisone, cortisone, prednisolone, and prednisone.

Antimicrobial agents suitable for use in the disclosed compositions include, but are not limited to, antibiotics such as aminoglycosides such as gentamycin, kanamycin, neomycin, and vancomycin; amphenicols such as chloramphenicol; cephalosporins, such as cefazolin HCl; penicillins such as ampicillin, penicillin, carbenicillin, oxycillin, methicillin; lincosamides such as lincomycin; polypeptide antibiotics such as polymixin and bacitracin; tetracyclines such as tetracycline; quinolones such as ciproflaxin, etc.; sulfonamides such as chloramine T; and sulfones such as sulfanilic acid as the hydrophilic entity; as well as anti-viral drugs, e.g. acyclovir, gancyclovir, vidarabine, azidothymidine, dideoxyinosine, and dideoxycytosine. Antifungal agents and any other opthalmically suitable antimicrobials are contemplated herein as well.

Methods of Treatment

Compositions disclosed herein may be used to treat patients suffering from keratoconjunctivitis sicca or meibomian gland disease or blepharitis. In some embodiments, the compositions disclosed herein can alleviate one or more symptoms of those conditions, such as, but not limited to, ocular dryness, eye irritation, soreness, redness and an accumulation of matter on the eyelids. Methods of treatment can include topical administration of one or more drops of the compositions disclosed herein into the eye of a patient in need thereof. According to some embodiments, methods of treatment of keratoconjunctivitis sicca or meibomian gland disease or blepharitis using androgen-containing compositions disclosed herein can result in reduced ocular irritation as compared to treatment with a vehicle (e.g., a composition not containing an androgen).

Table 2, 3, and 4 provide non-limiting exemplary eye drop, cream, and film formulations, respectively.

TABLE 2 Ingredient Function % w/w testosterone active 0.03 castor oil lipophilic vehicle 2.0 Pemulen TR-1 emulsifier 0.15 polysorbate 80 emulsifier 0.1 sodium hydroxide neutralizing Agent QS pH 7.3 Glycerin demulcent/tonicty agent 1.0 mannitol tonicity 2.0 PURITE ® preservative 0.01 Water hydrophilic vehicle QS 100

TABLE 3 Ingredient Function % w/w testosterone active 0.05 squalane lipophilic vehicle 12.0 diethylene glycol monoethyl lipophilic vehicle 3.0 ether Pemulen TR-1 emulsifier 0.1 Polsorbate 80 emulsifier 0.1 Carbomer thickener 0.1 Sodium hydroxide neutralizing Agent QS pH 6.5 PURITE ® preservative 0.01 Water hydrophilic vehicle QS 100

TABLE 4 Ingredient Function % w/w testosterone active 0.05 squalane lipophilic vehicle 10 diethylene glycol monoethyl lipophilic vehicle 10 ether Pemulen TR-2 emulsifier 0.2 Glycerin plasticizer 4.0 Isostearyl alcohol plasticizer 1.0 acrylate/octylacrylamide film former 2.5 copolymer Carbomer thickener 0.1 Sodium hydroxide neutralizing agent QS pH 6.5 PURITE ® preservative 0.01 Water hydrophilic vehicle QS 100

Tables 5 and 6 set forth additional non-limiting exemplary formulations contemplated by the practice of the invention.

TABLE 5 Formulation Formulation Ingredient Grade A B Testosterone USP, 0.02 0.03 PhEur Castor oil USP, 0.25 0.5 PhEur Polyoxyl 40 stearate NF, PhEur 0.25 0.5 Polysorbate 80 USP, 0.25 0.5 PhEur Sulfobutyl ether-β- 0.25 0.3 cyclodextrin (Captisol ®) Glycerin USP, 1.5 1.5 PhEur Carbomer copolymer type A NF 0.1 0.1 (Pemulen ™ TR2) Boric acid NF 0.6 0.6 Sodium hydroxide USP, q.s to pH 7.4 q.s to pH 7.4 PhEur Purified water USP, qs qs PhEur

TABLE 6 C D E F G Vehicle Ingredient % (w/w) % (w/w) % (w/w) % (w/w) % (w/w) % (w/w) Testosterone 0.01 0.02 0.03 0.1 0.3 0.00 Castor oil 0.25 0.25 0.25 0.25 0.25 0.25 Polyoxyl 40 0.25 0.25 0.25 0.25 0.25 0.25 stearate Polysorbate 80 0.25 0.25 0.25 0.25 0.25 0.25 Sulfobutyl ether-β- 0.12 0.25 0.36 1.25 3.75 3.75 cyclodextrin (Captisol ®) Glycerin 1.5 1.5 1.5 1.5 1.0 1.0 Carbomer 0.1 0.1 0.1 0.1 0.1 0.1 copolymer type A (Pemulen ™ TR2) Boric acid 0.6 0.6 0.6 0.6 0.6 0.6 Sodium hydroxide Q.S to Q.S to Q.S to Q.S to Q.S to Q.S to pH 7.4 pH 7.4 pH 7.4 pH 7.4 pH 7.4 pH 7.4 Purified water Q.S. Q.S. Q.S. Q.S. Q.S. Q.S.

EXAMPLES

The inventors have surprisingly discovered that testosterone containing formulations were better tolerated, showing less discomfort, than formulations comprising vehicle alone. Ocular discomfort is typically associated with a vehicle, drug, or combination of both. When it is related to a vehicle, discomfort is generally observed at comparable incidences (frequencies) and severity independent of drug concentrations. When it is related to a drug, discomfort observation incidence increases and/or severity gets worse with increasing drug concentrations. It is highly unexpected that discomfort is observed at decreased incidences with drug containing formulations relative to those with the vehicle.

To evaluate ocular discomfort, 3 groups of female rabbits (3/group) were treated in the left eye with a topical ocular drop (˜30 μL) of the testosterone formulation at a concentration of 0.03%, 0.1%, or 0.3% (formulations E, F, and G, described in table 6, above), 3 times daily (at 3-hour intervals) for 7 consecutive days. Using the same dosing regimen, a control group (3 females) was treated with the vehicle (also described at Table 6) corresponding to the 0.3% testosterone formulation. The right eye served as an untreated control. Ocular discomfort was evaluated on each treated eye immediately following each instillation on Days 1 (first treatment day), 3, and 7. Both severity (none<minimal<mild<moderate<severe) and duration of discomfort were evaluated.

Vehicle-related ocular discomfort (minimal) was observed in all dose groups. Throughout the treatment period collectively, discomfort was observed at a frequency of 52% with the vehicle (14 times out of 27 post-instillation measurements on Days 1, 3, and 7 combined); data from day to day and Days 1, 3, and 7 combined were comparable. In contrast, discomfort was observed at markedly decreased frequencies of 4% to 11% at ≥0.03% testosterone; data among different drug concentrations were comparable. In all dose groups, discomfort lasted up to 30 seconds. These results are illustrated in FIG. 1.

Certain embodiments of this invention are described herein. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the invention so claimed are inherently or expressly described and enabled herein.

In closing, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the present invention may be utilized in accordance with the teachings herein. Accordingly, the present invention is not limited to that precisely as shown and described.

Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the invention so claimed are inherently or expressly described and enabled herein. 

What is claimed is:
 1. A method of treating meibomian gland disease, the method comprising topical ocular administration of a composition, the composition comprising: Testosterone at a concentration between about 0.01% (w/w) and about 5.0% (w/w); Castor oil at a concentration between about 0.10% (w/w) and about 5% (w/w); a cyclodextrin at a concentration between about 0.25% (w/w) and about 10% (w/w); a C10-30 alkyl acrylate crosspolymer at a concentration between about 0.01% (w/w) and about 5% (w/w); Polyoxyl 40 stereate at a concentration between about 0.01% (w/w) and about 5% (w/w).
 2. The method of claim 1, wherein the testosterone is present in the composition at a concentration of between about 0.01% (w/w) and about 1% (w/w).
 3. The method of claim 2, wherein the testosterone is present in the composition at a concentration of between about 0.01% (w/w) and about 0.5% (w/w).
 4. The method of claim 3, wherein the testosterone is present in the composition at a concentration of about 0.03% (w/w), about 0.1% (w/w), or about 0.3% (w/w).
 5. The method of claim 4, wherein the castor oil is present in the composition at a concentration of between about 0.10% (w/w) and about 5% (w/w).
 6. The method of claim 5, wherein the castor oil is present in the composition at a concentration of between about 0.10% (w/w) and about 1% (w/w).
 7. The method of claim 6, wherein the castor oil is present in the composition at a concentration of between about 0.10% (w/w) and about 0.5% (w/w).
 8. The method of claim 7, wherein the castor oil is present in the composition at a concentration of about 0.25% (w/w).
 9. The method of claim 8, wherein the cyclodextrin is sulfobutyl ether-β-cyclodextrin present in the composition at a concentration of between about 0.25% (w/w) and about 5% (w/w).
 10. The method of claim 9, wherein the sulfobutyl ether-β-cyclodextrin is present in the composition at a concentration of between about 0.25% (w/w) and about 5% (w/w).
 11. The method of claim 10, wherein the sulfobutyl ether-β-cyclodextrin is present in the composition at a concentration of about 0.36% (w/w), 1.25% (w/w), or about 3.75% (w/w).
 12. The method of claim 11, wherein the C10-30 alkyl acrylate crosspolymer is present in the composition at a concentration of between about 0.01% (w/w) and about 1% (w/w).
 13. The method of claim 12, wherein the C10-30 alkyl acrylate crosspolymer is present in the composition at a concentration of about 0.1% (w/w).
 14. The method of claim 13, wherein the Polyoxyl 40 stearate is present in the composition at a concentration of between about 0.01% (w/w) and about 2% (w/w).
 15. The method of claim 14, wherein the Polyoxyl 40 stearate is present in the composition at a concentration of between about 0.01% (w/w) and about 1% (w/w).
 16. The method of claim 15, wherein the Polyoxyl 40 stearate is present in the composition at a concentration of about 0.25% (w/w).
 17. The method of claim 16, wherein the composition further comprises Polysorbate 80 at a concentration of between about 0.01% (w/w) and about 5% (w/w).
 18. The method of claim 17, wherein the Polysorbate 80 is present in the composition at a concentration of between about 0.01% (w/w) and about 1% (w/w).
 19. The method of claim 18, wherein the Polysorbate 80 is present in the composition at a concentration of about 0.25% (w/w). 